Polycystic kidney disease (PKD) is a group of disorders manifested by the development of large epithelial-lined cysts which grow from the nephrons and collecting ducts of kidney tubules. PKD can be inherited as an autosomal dominant (ADPKD) or autosomal recessive (ARPKD) trait, or can be provoked by environmental factors (acquired PKD). In humans, ADPKD is expressed with nearly complete penetrance and is a relatively common genetic disease. ADPKD is associated not only with renal failure, but also with liver cysts and cerebral aneurysms indicating that it is not localized specifically to the kidney. Acquired PKD occurs in high proportion of long-term renal dialysis patients, and is associated with a high frequency of adenomas and renal cell carcinomas. All forms of PKD have epithelial hyperplasia in common, and consequently it has been hypothesized that polycystic cells have lost normal growth controls. As a result, they may display certain characteristics of proliferating cells, such as those found in embryonic tissues, adult tissues that normally are active in cell division, or in regenerating tissues such as the liver following partial hepatectomy. It is also possible that polycystic cells have characteristics of preneoplastic or neoplastic cells. The principal aim of this research is to explore the molecular basis of the abnormal growth control in PKD, to learn more about the genetic and molecular events responsible for the cellular hyperplasia associated with these diseases, and to determine whether this hyperplasia is related to a normal proliferative response or to the process of neoplastic transformation. It is expected that polycystic cells will show differences relative to normal cells in the expression of genes associated with cell division, cell proliferation, or cellular growth regulation, and in other genes that may be secondarily affected by the abnormality. The levels of a number of proto-oncogene transcripts will be assayed by quantitative dot-blot, northern, and in situ hybridization to determine whether elevated oncogene expression is associated with PKD, and whether the expression of specific oncogenes is characteristic of the particular types of PKD. cDNA cloning will be utilized to identify mRNAs representing genes expressed at elevated levels specifically in human ADPKD, and in a mouse model for ARPKD. Polycystic kidney cells in culture will be used to determine the growth factor requirements and the response to growth factors of these cells to determine the extent to which the growth characteristics of polycystic cells resemble those of cultured transformed cells. These experiments should help to elucidate the molecular basis of cellular growth control in the kidney, and ultimately the primary genetic lesions responsible for the various forms of polycystic kidney disease.